Osteoporosis is the most common debilitating bone disease affecting 24 million people in the U.S. An estimated 50 percent of women over 45 and 90 percent of women over 75 years of age have osteoporosis, of which approximately half will suffer osteoporotic fractures. The estimated cost of osteoporosis and related fractures is 7-10 billion dollars per year. Bone resorption by osteoclasts is an energy intensive process, requiring ATP hydrolysis by an H+-ATPase to drive proton secretion. Age-dependent changes in bone mass are accompanied by age-dependent changes in other parameters, including glucose intolerance. Osteoclasts are glucose responsive cells that resorb bone in a glucose concentration dependent manner with a Km of 3 mM. The data presented here indicate that osteoclasts have glucose concentration dependent changes in 1) ATP synthesis, 2) phosphate uptake, 3) tyrosine phosphorylation, and 4) phosphatidylinositol 3-kinase activity. In view of the high metabolic demands of bone resorption, I hypothesize that glucose directly alters the activity of osteoclasts by modulating critical signal transduction processes in these cells. The proposed research will define the molecular mechanisms and metabolic requirements responsible for regulating these signal transduction processes. The Specific Aims are to: I: Characterize The Expression Of Glucose Transport Protein (S) In Osteoclasts. A. Determine the effect of bone attachment on GLUT2 expression in osteoclasts. B. Determine whether glucose transporters are translocated to the plasma membrane in response to bone attachment. II: Characterize Metabolic Elements That Govern Osteoclast Activity. A. Determine the rate limiting steps in glucose metabolism by osteoclasts. B. Characterize the glucose dependence of metabolic pathways. III: Identify Ket Signaling Pathways That Regulate Osteoclast Metabolism. A. Determine and characterize the role of glucose in osteoclastic phosphatidylinositol-dependent signaling pathways. B. Determine the role of glucose in modulating changes in tyrosine phosphorylation of specific proteins.